(1)The trace element vanadium can act like insulin, a major regulator of lipid metabolism. We demonstrated that in vitro, vanadium at concentrations as low as 250nM significantly reduces synthesis of the major atherogenic protein apoliprotein B-100 in Caco-2 cells (an intestinal human cell line). In addition, another form of apoB, apoB-48, considered non-athereogenic, is increased by vanadium. Vanadium is known to be a non-specific phosphatase inhibitor. To further evaluate the molecular mechanism various specific kinase activators and phosphatase inhibitors are being evaluated. In a pilot in vivo study, a rabbit model of familial hyper cholesterolemia (Watanabe breed) with elevated cholesterol, triglycerides and antherosclerosis was fed vanadate. A reduction was seen in cholesterol, triglyceride and apolipoprotein B as well as an increase in HDL cholesterol, the so called "good cholesterol." A follow-up study with 10 rabbits as well as rats as well will be done to further delineate the physiologic effects of vanadium. (2)We have begun a study has begun evaluating the effect of niacin, a lipid lowering drug, on the markedly atherogenic lipoprotein Lp(a) in patients with sytematic lupus erthematosus (SLE); another study is evaluating thyroid hormone induced changes in Lp(a) in thyroid cancer patients. During treatment for thyroid cancer, thyroid hormone levels are iatrogenically varied, allowing the effect of high and low levels of thyroid hormone on LP(a) to be determined. We have begun a trial in these patients to examine the effect of niacin, another lip lowering drug on the markedly atherogenic lipoprotein Lp(a). A collaborative study involves determing lipid effects of IL-6 was done in normal individuals. A single dose of IL-6 reduced cholesterol, triglycerides and apolipoprotein B, Lp(a) did not changes. (3)We are also developing transgenic and knockout REPR mice using a new methodology--RNA/DNA hybrids. With this procedure the RNA targets the hybrid to a specific region in the genome, the DNA portion is thought to then induce a repair process to modify a single targeted base, resulting in the desired change within the genome. The method has been used to induce a single base change in cultured cells. We are now atempting to utilize mouse embryonic stem cells and are injecting the RNA/DNA hybrids into mouse oocytes to create new animal models.